Our long term objective is to understand how this regenerative hair cycling behavior is regulated at the molecular level, and to apply this knowledge toward regenerative medicine. Adult stem cells appear to be remarkably flexible in their ability to reconstitute different tissue lineages raising great interest in assessing the therapeutic potential of those stem cells. We recently found that the BMP pathway plays a significant regulatory role in hair follicle stem cell (hfSC) homeostasis. However, how BMP signaling integrates different activators and inhibitors to achieve a molecular network capable of cyclic activation of hfSCs is not known. On the basis of our preliminary results, we propose the existence of a self regulatory loop inside of the hfSCs. Using mouse genetic methods, for the first time we are able to address this question by ablating BMP signaling specifically in hfSCs and then isolate these stem cells for transcriptional analyses. We have seen that there is an inverse relationship between the expression levels of BMP and Wnt signaling pathways. Therefore, we hypothesize that there is a constant competitive cycling between activator and inhibitor activities in hfSCs population within the hair bulge micro-environment which is critical for maintenance of hfSCs homeostasis. hfSCs constantly sum up surrounding activator and inhibitor activities and its functional states shift stochastically between activated, oscillating nd quiescent states. When the balance favors activators, those hfSCs are activated towards hair germ cell characteristics. When sufficiently tilted toward inhibitors, hfSCs are quiescent. When balanced, overall homeostasis of the hfSC population is maintained with a stochastic probability to undergo cyclic activation and quiescence. Our hypothesis will be tested by the proposed research. PUBLIC HEALTH RELEVANCE: Adult stem cells appear to be remarkably flexible in their ability to reconstitute different tissue lineages raising great interest in assessing the therapeutc potential of those stem cells. Here we explore the role of the BMP pathway in maintaining the homeostasis of hair follicle Stem Cells between quiescence, oscillating and activated states. Our overall goal is to understand very basic processes that are important for skin stem cell regulation.